This proposal tests the hypothesis that the unusual sodium-activated K+ current controls synaptic integration in an unanticipated way which is widespread in the mammalian brain. As such, it may be a previously unrecognized factor in memory and learning. Sodium-activated K+ channels (KNa channels) are present in most areas of the brain and are prevalent in the cell bodies of many pyramidal cells. In mitral cells of the olfactory bulb, KNa channels are densely packed into the plasma membrane of the cell body. In mitral cells, the cell body is interposed between the dendritic tuft which inputs synaptic potentials and the axon initial segment which is one site of action potential initiation in these cells. If KNa channels in the cell body were constitutively active, incoming synaptic potentials from the glomerulus would be shunted by the high K+ conductance of the soma, never reaching the axon spike initiation zone. However, we have shown by heterologous expression that KNa channels are highly modulated by metabotropic signaling through the G-alphaQ signaling pathway. If similarly modulated in mitral and other cells, their activity could be largely blocked r unblocked by metabotropic signaling at the soma. Thus, KNa channels may be gate-keepers of synaptic integration in the olfactory bulb where they could either block or permit the generation of action potentials by incoming synaptic potentials. This proposal aims to test the hypothesis that (1) KNa channels present in the cell bodies of mitral cells are indeed regulated by metabotropic signaling and (2) KNa channels must be down-regulated to permit the cell to generate an action potential. KNa channels are found in the plasma membrane of neuronal soma throughout the nervous system and could well be an important factor governing the intrinsic excitability of many cells; the intrinsic excitability of a neuron is increasingly undersood to be an important factor in synaptic integration and plasticity, and may be an important non-synaptic factor in memory and learning. These studies may provide a better understanding and treatment of disease which leads to deficits in learning and memory loss, such as the multiple syndromes producing senile dementia.